1,3,4,9B-Tetrahydro-2H-indeno{8 1,2-c{9 pyridines

ABSTRACT

The present invention concerns novel heterocyclic compounds of the formula:   WHEREIN R1 is lower alkyl of one to four carbon atoms, cycloalkyl of five or six carbon atoms, phenyl, or phenyl monosubstituted by chlorine, bromine, fluorine, methoxy, methylthio or lower alkyl of one to four carbon atoms, and A is a straight or branched alkylene chain of one to four carbon atoms. The compounds exhibit central nervous system depressant properties and are useful in the treatment of overt and hidden aggression.

United States Patent [1 1 Ebniither et al.

l,3,4,9B-'l'ETRAHYDRO-2H-INDENO[ 1,2- C ]PYRIDINES Inventors: AntonEbniither, Arlesheim;

Jean-Michel Bastian, Therwil; Erwin Rissi, Basel, all of SwitzerlandAssignee: Sandoz Ltd., Basel, Switzerland Filed: Nov. 29, 1973 Appl.No.: 419,991

Related u.s. Application Data Continuation-impart of Ser. No. 264,423,June 20, I972, abandoned, Confinuatiomin-part of Ser. No. 72,800, Sept.I6, I970, abandoned.

Foreign Application Priority Data Sept. 23, I969 Switzerland l43l7/69Dec. [8, I969 Switzerland 18830169 Apr. 23, 1970 Switzerland 6078/70June 3, I970 Switzerland 8267/70 Sept. 23, I969 Switzerland 14318/69Dec. 16, I969 Switzerland [8671/69 Apr. 23, I970 Switzerland 6079/70June 3, I970 Switzerland 8268/70 Sept. 23, I969 Switzerland.......l43l9/69 Apr. 23, I970 Switzerland........... 6080/70 June 3, I970Switzerland 8269/70 US. Cl 260/293.54; 424/267 Int. Cl. C07D 221/16Field 0! Search 260/293.54

[ Dec. 23, 1975 [56] References Cited UNITED STATES PATENTS 3,573.3 l63/l97i Ebniither et al. 260/294] Primary Examiner-G. Thomas ToddAttorney, Agent, or Firm-Gerald D. Sharkin; Robert S. Honor [57]ABSTRACT The present invention concerns novel heterocyclic compounds ofthe formula:

[FA-C041 The compounds exhibit central nervous system depressantproperties and are useful in the treatment of overt and hiddenaggression.

33 Claims, No lk'awings l,3,4,9B-TETRAHYDRO-2H-INDENOl l,2-C]PYRI- DlNESThis is a continuation-in-part of our copending appli- 5 cation Ser. No.264,423 filed June 20, [972, now abandoned, which in turn is acontinuation-in-part of our application Ser. No. 72,800 filed Sept. 16,I970, now abandoned.

The invention provides new heterocyclic compounds m of formula I,

N--AC-R wherein R, is lower alkyl ofone to four carbon atoms, cycloalkylof five or six carbon atoms, phenyl, or phenyl monosubstituted bychlorine, bromine, fluorine, methoxy, methylthio or lower alkyl of oneto four carbon atoms, and A is a straight or branched alkylene chain ofone to four carbon atoms, and processes for the production thereof.

In accordance with the invention the new compounds of formula I areobtained by u. reacting the compound of formula ll,

or a salt thereof, with a compound of formula III,

X-A--CO- R, wherein R and A are as defined above, and X is the acidradical of a reactive ester, in an inert solvent and in the presence ofan acid-binding agent, or

b. reacting the compound of formula II, or a salt thereof, with acompound of formula Illa,

k CH l CO- k, Illa in an inert solvent, to produce a compound of formulala,

N-CH CH-JJO-Ji i I Ia wherein the above formulae llla and In R R and Rare hydrogen, or alkyl of one to two carbon atoms. and R, is as definedabove, or

2 c. reacting the compound of formula II, or a salt thereof, withformaldehyde and a compound of formula lllb,

R., cH- .Co-R,' wherein R is as devined above, and R, is tertiary loweralkyl, phenyl, or phenyl monosubstituted by chlorine, bromine. fluorine,methoxy, methylthio or lower alkyl of one to four carbon atoms, in aneutral or weakly acid inert solvent medium, under the conditions of aMannich reaction, to produce a compound of formula lb,

wherein R, and R are as defined above.

Process (a) may, for example, be effected by reacting the compound offormula ll, or a salt thereof, with a compound of formula III,preferably a compound lll wherein X is chlorine, bromine, methyl orp-toluenesulphonic acid, in an inert solvent, e.g. an aromatichydrocarbon such as toluene or benzene, or a chlorinated hydrocarbonsuch as chloroform or carbon tetrachloride, or a di(lower)alkyl amide ofa lower carboxylic acid, such as dimethyl formamide, and in the presenceof an acid-binding agent, e.g. an alkali metal carbonate such as sodiumor potassium carbonate, or a tertiary base such as triethyl amine, or anexcess of the compound of formula II, at a temperature between 40 andl0OC, conveniently at the boiling temperature of the reaction mixture.

For example, the compound of formula ll and potassium carbonate may besuspended in dimethyl formamide, and a solution of a compound of formulaIll in the same solvent may be added at an elevated temperature, e.g. C,while stirring. After the reaction is complete, the reaction product maybe isolated and purified in known manner.

Process (b) may, for example, be effected by reacting a compound offormula ll with a compound of the formula Illa in an inert solvent, e.g.a lower alcohol such as ethanol, or a di(lower)alkyl amide of a lowercarboxylic acid, such as dimethyl formamide, preferably at an elevatedtemperature, e.g. at 50C to the boiling temperature of the reactionmixture. and optionally in the presence of an organic base such astriethyl amine and/or a strong basic catalyst, e.g. benzyl trimethylammonium hydroxide.

For example, the compound of formula ll and a compound of formula Illamay be dissolved in ethanol and the solution heated to C for about 2hours. After the reaction is complete, the reaction product may beisolated and purified in conventional manner.

Reaction of the compound of formula II, or its salts, with formaldehydeand a compound of formula lllb may, for example, take place at anelevated temperature, conveniently at a temperature between 50C and theboiling temperature of the reaction mixture. A lower alcohol such asethanol is preferably used as inert solvent when the substituent R, isphenyl or monosubstituted phenyl. When R, is tertiary lower alkyl,glacial 3 acetic acid is preferably used as solvent. Isolation of thereaction product may be effected in known manner.

The compounds of formula 1 may be administered in pharmaceuticallyacceptable acid addition salt form. Such salts possess the same order ofactivity as the free bases and are readily prepared in conventionalmanner. Suitable salts are organic salts such as the acetate, succinateor benzeneor methane-sulphonate and inorganic salts such as thesulphate, hydrobromide or by drochloride.

The straight or branched alkylene chain represented by the symbol Apreferably contains one to three carbon atoms.

The compounds of formula l and pharmaceutically acceptable acid additionsalts thereof are useful because they possess pharmacological propertiesin animals. In particular the compounds are useful in the treatment ofconditions of overt or hidden aggression as indicated by behaviouralstudies in mice on i.p. as well as p.o. administration of 3 mg/kg animalbody weight of the test compound, and in tests of aggressive behaviourinduced in the cat by electrical stimulation of particular areas of thehypothalmus, on i.p. as well as p.o. administration of l to 5 mg/kganimal body weight of the test compound. In the tests on mice,aggression is induced by isolating male mice for a minimum period offour weeks (Yen et al, J. Pharmacol. Exp. Ther. 122, 85A 1958) and themice exhibit typical patterns of offensive aggressive behaviour when twoof them are placed together in a cage. Aggressive behaviour was alsoinduced in mice by electric shock (Tedeschi et al, J. Pharmacol. Exp.Ther. 125, 28, 1959), in which the mice take up a characteristicdefensive position, considered as a defensive aggression reaction. itwas found that offensive aggression was inhibited at lower dosages thandefensive aggression was inhibited so that the compounds can be regardedas being specific in action. Sedation was measured by standard tests onmotor activity in mice (light-beam cage, climbing test and rotarod) andit was shown that inhibition of motor activity does occur. The compoundsalso are devoid of significant anti-depressant activity at the lowdosages where inhibition of isolation-induced aggression occurs.Anti-depressant activity involving central nervous stimulation isclearly a property highly undesirable in an anti-aggressive agent. Thepsychopharmacological properties of the compounds indicate they aresuitable in the treatment of conditions in which sedation and inhibitionof aggression are desirable, such as in aggressive behaviour in erethicoligophrenics and aggressive behaviour in psychotics and possibly inpsychopaths.

For the abovementioned use, the dosage administered will naturally varydepending on the compound employed, the mode of administration and thetreatment desired. However. in general. satisfactory results areobtained at daily doses between about 0.1 and about milligrams perkilogram animal body weight, conveniently given in divided doses two tothree times a day or in sustained release form. For the larger mam mals,the total daily dose is from about 5 to about 500 milligrams, and dosageforms suitable for oral administration comprise from about 2 to about250 milligrams of the compound, in association with a solid or liquidpharmaceutical carrier or diluent. Thus the compounds of formula 1, ortheir pharmaceutically acceptable acid addition salts, may beadministered orally in such forms as tablets, capsules, elixirs,suspensions and the like, or

parenterally in the form of an injectable solution or suspension.

The production of the starting materials may be cffected in accordancewith known processes or in a manner analogous to known processes. Thecompound of formula ll may be prepared as described in the last of thefollowing Examples. Free base forms of the compounds of formula I are,for example, obtained by treating the pure, crystalline, e.g.hydrochloride, salt forms with potassium carbonate, extracting withchloroform and evaporating to a residue. The free base forms of thecompounds of formula I are useful intermediates for the preparation, inconventional manner, of pharmaceutically acceptable acid addition saltforms.

In the following Examples, which illustrate the invention without in anyway limiting its scope, all temperatures are indicated in degreesCentigrade and are uncorrected.

EXAMPLE 1 2-Acetonyll ,3,4,9b-tetrahydro-5-methyl-2H indeno[l,2-c]pyridine A mixture of 20.6 g of l,3,4,9b-tetrahydro-5-methyl-2H-indeno[ 1,2-c]pyridine, 18.4 g of potassium carbonate and 10.7 cc ofchloro acetone in 130 cc of dry chloroform is heated to the boil for 17hours while stirring. After cooling the reaction mixture is filtered andthe filtrate is washed with water. Drying is effected over magnesiumsulphate, the solvent is removed by evaporation and the residue isdissolved in ethanonl. The calculated amount of hydrochloric acid inethanol is added and the mixture is allowed to crystallize. Pure2-acetonyll ,3 ,4,9b-tetrahydro-5-methyl-2H- indeno[ l ,2-clpyridinehydrochloride, having a MP. of 2l42l5, is obtained without furtherpurification.

EXAMPLE 2 l,3,4,9b-Tetrahydro-5-methyl-2-( 2-oxophenethyl )2H- indeno[l,2-c]pyridine A solution of l2.2 g of phenacyl chloride in 25 cc ofdimethyl formamide is added dropwise at while stirring to a suspensionof 15.8 g of l,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l ,2-clpyridinehydrochloride and 2l.65 g of potassium carbonate in 60 cc of dimethylformamide. The reaction mixture is allowed to react for a further hourat 70 and is then poured into 1000 cc of water. The reaction mixture ismade strongly alkaline with a dilute sodium hydroxide solution, isextracted with benzene, and the extracts are dried over magnesiumsulphate. The residue obtained after removing the solvent by evaporationis dissolved in ethanol and the calculated amount of hydrochloric acidin ethanol is added. The reaction solution is diluted with ether untilit becomes slightly turbid and is then allowed to crystallize slowly.Pure l,3,4,9b-tetrahydro-5-methyl 2-( 2-oxophenethyl )-2H-indeno[ l,2-clpyridine hydrochloride, having a MP. of 202205 (decomp. is obtained.

The following compounds of formula I (Examples 3 to 7) may likewise beobtained in a manner analogous to that described in Example 2:

EXAMPLE 3 1,3,4,9b-Tetrahydro-5-methyl-2( 5-methyl-3-oxohexyl)-2H-indeno[ l,2-c ]pyridine MP. of the hydrochloridel84l86 (decomp).

EXAMPLE 4 l,3,4.9b-Tetrahydro-5-methyl-2-( 3-oxobutyl l-ZH- indeno[l,2-c]pyridine M.P. of the hydrogen fumaratel8$l86 with decompositionafter a previous M.P. of 144.

M.P. of the methane sulphonatel 60.5-l6] .5 (de- Comp).

M.P. of the hydrochloridel64l66 (decomp.).

The title compound of this example is an effective antiaggressive agentwhen administered orally or parenterally to an animal in need of suchtreatment at a dosage of I mg twice per day.

EXAMPLE l.3,4.9b-Tetrahydro-5-methyl-2-( 2-methyl-3- oxobutyl)-2H-indeno[ l,2-c]pyridine MP. of the hydrochloridel80-l82 (decomp.).

EXAMPLE 6 l.3,4,9b-Tetrahydro-5-methyl-2-( 3-oxopentyl )-2H- indeno[ l,2-c ]pyridine M.P. of the hydrochloridel76l78 (decomp.).

EXAMPLE 7 l 3 4.9bTetrahydro-5-methyl-2-( 4,4-dimethyl-3- oxopcntyl)-2H-indeno[ l ,2-c]pyridine M.P. of the hydrochloridel93l94 (decomp.).

EXAMPLE 8 l,3,4.9b-Tetrahydro-5-methyl-2-( 4-methyl-3-oxopentyl)-2H-indeno[ l,2-c]pyridine.

A solution of l3.2 g of l-chloro-4-methyl-3-pentanone is added dropwiseat 50 within 2 hours while stirring to a suspension of I80 g ofl,3.4,9b-tetrahydro-5-methyl-2H-indeno[ l ,2-clpyridine hydrochloride,28.] g of potassium carbonate and L3 g of potassium iodide in 200 cc ofdimethyl formamide. The reaction mixture is allowed to react at 50 for afurther hour and is then diluted with 500 cc of benzene. Ex traction iseffected thrice with water, the organic phase is dried over magnesiumsulphate and the solvent is removed by evaporation. The residue isdissolved in acetone and the calculated amount of hydrochloric acid inethanol is added. After recrystallization of the resulting crudecrystalline product from methanol/ether, the hydrochloride of the titlecompound. having a M.P. of l80-l82 (decomp.), is obtained.

The following compounds of formula 1 (Examples 9 and may be obtained ina manner analogous to that described in Example 8:

EXAMPLE 9 l,3.4,9b-Tetrahydro-5-methyl-2-( 4-oxopentyl )-2H- indeno[ l,2-c1pyridine M.P. of the hydrochloridel86l88.

EXAMPLE 10 2-(4-p'Fluorophenyl-4 oxobutyl )-l .3 4.9b-tetrahydroS-methyl-ZH-indenol 1.2-clpyridine M.P. of the hydrochloride 227229.

EXAMPLE 1] 2-( 3-Cyclopentyl-S-oxopropyl )-l ,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l,2-c]pyridine A solution of 19.6 g ofl-chloro-3-cyclopentyl-3- propanone in 50 cc of dimethyl formamide isadded dropwise at a temperature of 50 while stirring to a solution of18.0 g of l,3,4,9b-tetrahydro-5-methyl2H- indeno[ l .2-c]pyridinehydrochloride and 20.0 g of triethyl amine in 100 cc of dimethylformamide. The reaction mixture is subsequently allowed to react at thesame temperature for a further 10 minutes and is then diluted withbenzene. The reaction mixture is extracted 4 times with water and theorganic phase is dried over magnesium sulphate. The solvent is removedby evaporation at reduced pressure, the residue is dissolved in methanoland the calculated amount of hydrochloric acid in ethanol and ether areadded. The resulting crystalline product is again recrystallized frommethanol/ether. M.P. of the hydrochloride l96-l98 (decomp.).

The following compounds of formula I (Examples ]2 to 16) may be obtainedin a manner analogous to that described in Example 1 1:

2-p-Bromophenacyll ,3 ,4,9b-tetrahydro-5-methyl-2H- 4U indeno[ l,2-c]pyridine M.P. of the hydrochloride-233235 (decomp.) fromisopropanol/water.

EXAMPLE l 5 Z-p-Chlo rophenacyl- ,3,4,9b-tetrahydro-5-methyl-2l-lindeno[l ,2-c]pyridine M.P. of the hydrochloride230-232 (decomp) from methanol.

EXAMPLE l6 l,3,4,9b-Tetrahydro-Z-p-methoxyphenacyl-S-methyl- 2H-indenoll ,2c]pyridine M.P. of the hydrochloride22l223 from ethanol.

EXAMPLE l7 l,3,4,9b-Tetrahydro-5-methyl-2-( 3-oxobutyl )-2H- indeno[l,2-c]pyridine A solution of 10.0 g of l,3,4,9b-tetrahydro-5-methy1-ZH-indenol l,2-c]pyridine and 4.54 g of methyl vinyl ketone in 150 cc ofethanol is heated to for2 hours. The mixture is evaporated to dryness,the residue is again dissolved in a small amount of ethanol, and thecalculated amount of hydrochloric acid in ethanol is added. Theresulting crystalline product is again recrystallized from ethanol andyields pure 1.3.4.9b-tetrahydro 5methyl 2-( 3-oxobutyl )QH-indenol l.2-clpyri 7 dine hydrochloride having a M.P. of l64l66 (decomp.

The following compounds of formula I (Examples 18 to 20) may likewise beobtained in a manner analogous to that described in Example 17:

EXAMPLE 18 l .3,4,9b-Tetrahydro-5-methyl-2-( 4,4-dimethyl-3- oxopentyl)-2H-indeno[ l ,2-c1pyridine M.P. of the hydrochloride-l93194 (decomp).

EXAMPLE l9 2-( 3-Cyclopentyl-3-oxopropyl I ,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l,2-c]pyridine M.P. of the hydrochloridel96-l98(decomp).

EXAMPLE 20 2-( 3Cyclohexyl-3-oxopropyl l ,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l ,2-clpyridine M.P. of the hydrochloridel94-196(decomp).

EXAMPLE 2] l,3,4,9b-Tetrahydro-5-methyl-2-( 2-methyl-3-oxbutyl)-2H-indeno[ l.2-c]pyridine A solution of 14.5 g ofl,3,4,9b-tetrahydro--methyl- ZH-indenol l,2-c[pyridine and 7.9 g ofisopropenyl methyl ketone in ISO cc of ethanol is kept at roomtemperature for l6 hours and subsequently at 80 for 2 hours. The ethanolis removed by evaporation, the residue is taken up in benzene andfiltration is effected through a layer of aluminium oxide. The residueobtained after concentrating the benzene solution by evaporation isdissolved in acetone and the calculated amount of hydrochloric acid inethanol is added. After recrystallization of the resulting crudehydrochloride from ethanol the hydrochloride of the title compound isobtained in pure form having a M.P. of l80l82 (decomp.):

EXAMPLE 22 l ,3,4,9b-Tetrahydro-5-methyl-2-( 3-oxopentyl )-2H- indeno[l,2-c[pyridine The hydrochloride of the title compound, having a M.P. ofl76-l78 (decomp), is obtained in a manner analogous to that described inExample 2].

EXAM PLE 23 l,3,4,9b-Tetrahydro-5-methyl-2-(5-methyl-3-oxohexyl)-2H-indeno[ l,2-c]pyridine A solution of 13.7 g ofisobutyl vinyl ketone in 30 cc of dimethyl forrnamide is added dropwiseat a temperature of 60 while stirring to a solution of 18.0 g ofl.3,4,9b-tetrahydro-S-methyl-2H-indeno[ l ,2-c ]pyridine hydrochlorideand 9.05 g of triethyl amine in 150 cc of dimethyl formamide. Thereaction mixture is allowed to react at the same temperature for afurther minutes and is subsequently diluted with 500 cc of benzene. Thereaction mixture is repeatedly extracted with water and the organicphase is dried over magnesium sulphate. The residue obtained afterremoving the solvent by evaporation is dissolved in methanol and thecalculated amount of hydrochloric acid in ethanol and ether are added.The resulting crystalline product is again recrystallized frommethanol/ether. MP. of the hydrochloride l 84- 1 86 (decomp.

8 The following compounds of formula 1 (Examples 24 to 26) may likewisebe obtained in a manner analogous to that described in Example 23;

EXAMPLE 24 2-( 3-p-Chlorophenyl-3-oxopropyl l ,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l ,2-c]pyridine The residueobtained after removing the solvent by evaporation is dissolved inmethanol and the calculated amount of hydrochloric acid in ethanol andether are added. The resulting crude hydrochloride is converted into thefree base by treatment with a potassium carbonate solution andextraction with chloroform, and the free base is purified byrecrystallizing twice from benzene/petroleum ether. M.P. 96-99.

EXAMPLE 25 2-( 3-p-Bromophenyl-3-ox0propyl)-l,3,4,9b-tetrahydro-S-methyl-ZH-indenol l ,2-c1pyridine Isolation asindicated in Example 24. M.P. l20-l24 from benzene/petroleum ether.

EXAMPLE 26 l ,3,4,9b-Tetrahydro-2-( 3'p-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indeno[ l ,2-c]pyridine Isolation as indicated in Example24. M.P. 9597 from benzene/petroleum ether.

EXAMPLE 27 l,3,4,9b-Tetrahydr0-5-methyl-2-(3-oxo-3phenylpropyl)-2H-indenol[ l,2-c ]pyridine A suspension of 7.0 gof l,3,4,9b-tetrahydro-5-methyl-2H-indenoll,2c]pyridine hydrochloride,4.9 g of acetophenone and 9.5 g of paraformaldehyde in I20 cc of ethanolis heated to the boil while stirring for l8 hours. The reaction mixtureis filtered, the filtrate is evaporated to dryness and the resultingresidue is re crystallized from ethanol/petroleum ether. M.P. of thehydrochloride l 84l 85.

EXAMPLE 28 2-( 3-p-Fluorophenyl-3-oxopropyl )-l,3,4,9b-tetrahydro5-methyl-2H-indeno[ l ,2-c ]pyridine A mixture of 18.0g of l,3,4,9b-tetrahydro'5-methyl- 2H-indeno[ l,2-c[pyridinehydrochloride, l0.2 g of p-fluoro-acetophenone and 2.75 g ofparaformaldehyde in cc of ethanol is heated to the boil at reflux whilestirring for 1 hour. A further 2.75 g of paraformaldehyde are added, themixture is allowed to boil at reflux for l hour, and a further 5.5 g ofparaformaldehyde are subsequently added. The mixture is allowed to reactat the boil for a further 4 hours and is subsequently cooled on ice. Theresulting crystalline product is further purified by recrystallizingtwice from ethanol/water and once from methanol. M.P. of thehydrochloride 200203.

The following compounds of formula I (Examples 29 to 34) may likewise beobtained in a manner analogous to that described in Example 28:

Example 29 1.3 .4.9 b-Tetrahydro-5-methyl-2-( 3-oxo-3-m-tolylpropyl)-2H-indeno[ l,2-c ]pyridine M.P. of the hydrochloridell 82 (decomp).

EXAMPLE 3(] l,3,4,9b-Tetrahydro-5-methyl-(3-oxo-3-o-tolylpropyl)-2H-indeno[ 1,2-clpyridinc 5 The crudehydrochloride obtained from the reaction EXAMPLE 3]l,3,4,9b-Tetrahydro2-(3-m-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indeno[ l ,2-c ]pyridine M.P.of the hydrochloride-l83-l85 (decomp) from 95 /1 ethanol.

EXAMPLE 32 2-( 3-p-Chlorophenyl-3-oxopropyl l,3,4,9b-tetrahydro-5-methyl-2H-indenol l ,2c]pyridine The free base isproduced from the crude hydrochloride obtained from the reaction bytreatment with a potassium carbonate solution and extraction withchloroform, and this free base is purified by recrystallizing twice frombenzene/petroleum ether. M.P. 9699.

EXAMPLE 33 2-( 3-p-Bromophenyl-3-oxopropyl l,3,4,9b-tetrahydro-S-methyl-ZH-indeno[ l,2-c]pyridine M.P. l2()-124(working up as indicated in Example 32).

EXAMPLE 34 l ,3,4,9b-Tetrahydro-2-( 3-p-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indenol 1,2-c]pyridine M.P. 9597 (working up as indicatedin Example 32).

EXAMPLE 35 l ,3 ,4,9b-Tetrahydro-5-methyl-2-( 4,4-dimethyl-3- oxopentyl)-2H-indeno[ l,2-c jpyridine A mixture of 18.0 g of l,3,4,9b-tetrahydro-S-methyl- ZH-indenol l,2-c]pyridine hydrochloride,[0.6 g of pinacoline and 24.4 g of paraformaldehyde in lOO cc of glacialacetic acid is heated to l for 2 hours while stirring. The reactionmixture is subsequently evaporated to dryness and the resulting residueis taken up in water. The mixture is made alkaline by the addition ofsolid potassium carbonate, and extraction is effected with benzene. Thecrude base obtained after evaporat ing the dried benzene extracts isdissolved in acetone, and the calculated amount of hydrochloric acid inethanol is added. The resulting crystalline product is further purifiedby recrystallization from methanol/ether. M.P. of the hydrochloridel93-l94 (decomp).

The l,3,4,9b-tetrahyd ro-5-methyl-2H-indeno[ 1,2- cI-pyridine, employedin the above Examples, may be prepared as follows:

68.8 g of chloroformic acid ethyl ester are added dropwise whilestirring to a solution of 21 g of1,3,4,9btctrahydro-2,5dimethyl-2H-indeno[ 1.2-0 lpyridine in 90 cc ofabsolute benzene. The reaction solution is then heated to the boil for 4hours and after cooling to room temperature is extracted twice withwater and once with 2 N hydrochloric acid. The organic phase is driedover magnesium sulphate and concentrated by evaporation. The resultingresidue is distilled in a high vacuum, whereby pure Z-ethoxycarbonyl-l,3,4,9b-tetrahydro-5-methyl-2H-indeno[ l,2-c]pyridine, having a B.P. ofl43l45/0.02 mm of Hg, is obtained.

12 g of solid potassium hydroxide are added to a solution of 1 17 g of2-ethoxycarbonyll ,3,4,9b-tetrahydro-5-methyl-2H-indeno[l,2-c]pyridinein I20 cc of n-butanol, and the mixture is heated to the boil for 3hours. The reaction mixture is concentrated by evaporation on a rotaryevaporator, the residue is taken up in water and the solution isrepeatedly extracted with chloroform. The chloroform extracts are driedover magnesium sulphate and subsequently concentrated by evaporation.The resulting crude base is converted into the hydrochloride bydissolving the evaporation residue in ethanol and adding the calculatedamount of hydrochloric acid in ethanol. The solution is evaporated todryness and the residue is crystallized twice from ethanol/ether. Purel,3,4,9b-tetrahydro-5-methyl-2H- indeno[ l ,2-c]pyridine hydrochloridehas a M.P. of 182-l84.

The l,3,4,9 b-tetrahydro-2,S-dimethyl-ZH- indenol l ,2-c]-pyridine, usedas starting material, may be produced as follows:

a. 100 cc of a 4.4 solution of methyl lithium in ether is added dropwiseat 30 while stirring to a suspension of 32.2 g ofl,3,4,4a,5,9b-hexahydro-2-methyl- 2H-indeno[1,2-clpyridin-5-one in 300cc of absolute ether. After the addition is completed the reactionmixture is stirred at 20 for 3 hours, and cc of a 20 ammonium chloridesolution are added dropwise while cooling with ice and in an atmosphereof nitrogen, and the mixture is extracted with ether. The combined etherextracts are dried over magnesium sulphate, the magnesium sulphate isremoved by filtration and the filtrate is evaporated to dryness. Theresidue, a crystalline crude product, is recrystallized twice fromdiisopropyl ether, whereby purel,3,4,4a,5,9b-hexahydro-2,5-dimethyl-5(2H)-indeno[ l ,2-clpyridinol,having a M.P. of l32l34, is obtained.

12. A solution of 14 g of l,3,4,4a,5,9b-hexahydro-2,5-dimethyl-5(2H)-indeno[ l,2-c]pyridinol in 200 cc of a 5 N solution ofhydrogen chloride in ethanol is heated to the boil under reflux for 15minutes. The solution is subsequently evaporated to dryness. Afterrecrystallizing the residue twice from isopropanol purel,3,4,9btetrahydro-2,5-dimethyl-2H-indeno[ l ,2-clpyridinehydrochloride, having a M.P. of 203205 (decomp. is obtained.

What is claimed is:

l. A pharmaceutically acceptable acid addition salt of the formula:

l'l-A-CO-R V monosubstituted by chlorine, bromine, fluorine, methoxy,methylthio or lower alkyl of one to four carbon atoms, and

A is a straight or branched alkylene chain of one to four carbon atoms.

2. A compound of claim 1, wherein R, is phenyl, or phenylmonosubstituted by chlorine, bromine, fluorine, methoxy or lower alkylof one to four carbon atoms.

3. A compound of claim 1, wherein R, is cycloalkyl of five to six carbonatoms.

4. A compound of claim 1, wherein R is lower alkyl of one to four carbonatoms.

5. A pharmaceutically acceptable acid addition salt of the formula:

/ l rt-riu-ciu-co-a R2 R3 wherein R is lower alkyl of one to four carbonatoms, cycloalkyl of five or six carbon atoms, phenyl, or phenylmonosubstituted by chlorine, bromine, fluorine, methoxy, methylthio orlower alkyl of one to four carbon atoms, and

R and R are hydrogen, or alkyl of one to two carbon atoms.

6. The compound of claim 1, which isZ-acetonyll,3,4,9b-tetrahydro-S-methyl-2H-indenol l ,2-clpyridine.

7. The compound of claim 1, which is l,3,4,9b-tetrahydro-5-methyl-2-(2-oxophenethyl )-2H-indenol 1,2- clpyridine.

8. The compound of claim 1, which is l,3,4,9b-tetrahydro-S-methyl-2(5-methyl-3-oxohexyl )-2H- indeno[ l,2-c]pyridine.

9. The compound of claim 1, which is l,3,4,9b-tetrahydro-5-methyl-2-(6-oxobutyl )-2H-indeno[ l ,2- clpyridine.

10. The compound of claim 1, which is l,3,4,9b-tetrahydro-5-methyl-2-(2-methyl-3-oxobutyl )-2H- indeno[ l ,2-c ]pyridine.

II. The compound of claim 1, which is l,3,4,9b-tetrahydro-5-methyl-2-(3-oxopentyl)-2H-indenol 1,2- clpyridine.

12. The compound of claim I, which is l,3,4,9b-tetrahydro-5-methyl-2-(4,4-dimethyl-3-oxopentyl )-2H- indeno[ l,2-c ]pyridine.

13. The compound of claim 1, which is l,3,4,9b-tetrahydro-S-methyl-2-(4-methyl-3-oxopentyl )-2H- indeno[ l,2-c]pyridine.

14. The compound of claim 1, which isl,3,4,9b-tetrahydro-5-methyl-2-(4-oxopentyl )-2H-indeno[ 1,2-c]pyridine.

l5. The compound of claim I, which is 2-(4-pfluorophenyl-4-oxobutyl l,3,4,Qb-tetrahydro-S-methyI-ZH-indenol 1,2-c Ipyridine.

16. The compound of claim 1, which is 2-(3-cyclopentyl-S-oxopropyl l.3.4,9b-tetrahydro-S-methyl-ZH- indeno[ l ,2-c ]pyridine.

17. The compound of claim I, which is 2-(3- cyclohexyl-3-oxopropyl l,3,4,9b-tetrahydro-S-methyl-2H-indeno[ l,2-c]pyridine.

l8. The compound of claim 1, which isl,3,4,9b-tetrahydro-Z-m-methoxyphenacyl-S-methyl-2H- indeno( l ,Z-c]pyridine.

19. The compound of claim 1, which is 2-p-bromophenacyl- 1,3,4,9b-tetrahydro-5-methyl-2H- indeno[ 1 ,2c ]pyridine.

20. The compound of claim I, which is Z-p-chlorophenacyll,3,4,9b-tetrahydro-5-methyl-2H- indeno[ l ,2-c]pyridine.

21. The compound of claim 1, which isl,3,4,9b-tetrahydro-Z-p-lmethoxyphenacyl-]5-methyl-2H- indeno[ l,2-c]pyridine.

22. The compound of claim I, which is 2-( 3-pchlorophenyl-S-oxopropyl)-1,3 ,4,9b-tetrahydro-5- methyl2H-indeno[ l,2-c]pyridine.

23. The compound of claim 1, which is 2-( 3-pbromophenyl-3-oxopropyl l,3 ,4,9b-tetrahydro-5- methyl-2H-indeno[ l,2-c]pyridine.

24. The compound of claim 1, which is l,3,4,9b-tetrahydro-2-(3-p-methoxyphenyl-3-oxopropyl )-5-methyl-2H-indeno[ l,2-c]pyridine.

25. The compound of claim 1, which is l,3,4,9b-tetrahydro-S -methyl-2-(3-oxo-3-phenylpropyl )-2H- indeno[ l ,Z-clpyridine.

26. The compound of claim I, which is 2-(3-pfluorophenyl-3-oxopropyl l,3,4,9b-tetrahydro-5- methyI-ZH-indenol l ,2-clpyridine.

27. The compound of claim 1, which is l,3,4,9b-tetrahydro-5-methyl-2-(3-oxo-3-m-t0lylpropyl )-2H- indeno[ l ,2-c]pyridine.

28. The compound of claim 1, which is l,3,4,9b-tetrahydro-S -methyl-(3-oxo-3-o-tolylpropyl )-2H- indeno[ l ,2-clpyridine.

29. The compound of claim 1, which is l.3,4,9b-tetrahydro-2-(3-m-methoxyphenyl-3-oxopropyl )-5-methyl-2H-indeno[ l ,2-c]pyridine.

30. A free base of the formula:

N-A-CO-R yl-ZH-indenol l,2-c ]pyridine.

1. A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT OF THE FROMULA:
 2. Acompound of claim 1, wherein R1 is phenyl, or phenyl monosubstituted bychlorine, bromine, fluorine, methoxy or lower alkyl of one to fourcarbon atoms.
 3. A compound of claim 1, wherein R1 is cycloalkyl of fiveto six carbon atoms.
 4. A compound of claim 1, wherein R1 is lower alkylof one to four carbon atoms.
 5. A pharmaceutically acceptable acidaddition salt of the formula:
 6. The compound of claim 1, which is2-acetonyl-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 7. Thecompound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(2-oxophenethyl)-2H-indeno(1,2-c)pyridine.8. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(5-methyl-3-oxohexyl)-2H-indeno(1,2-c)pyridine.
 9. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(6-oxobutyl)-2H-indeno(1,2-c)pyridine.10. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(2-methyl-3-oxobutyl)-2H-indeno(1,2-c)pyridine.
 11. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(3-oxopentyl)-2H-indeno(1,2-c)pyridine.12. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(4,4-dimethyl-3-oxopentyl)-2H-indeno(1,2-c)pyridine.
 13. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(4-methyl-3-oxopentyl)-2H-indeno(1,2-c)pyridine.
 14. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(4-oxopentyl)-2H-indeno(1,2-c)pyridine.15. The compound of claim 1, which is2-(4-p-fluorophenyl-4-oxobutyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 16. The compound of claim 1, which is2-(3-cyclopentyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 17. The compound of claim 1, which is2-(3-cyclohexyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 18. The compound of claim 1, which is1,3,4,9b-tetrahydro-2-m-methoxyphenacyl-5-methyl-2H-indeno(1,2-c)pyridine.19. The compound of claim 1, which is 2-p-bromophenacyl-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 20. The compound ofclaim 1, which is 2-p-chlorophenacyl-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 21. The compound ofclaim 1, which is1,3,4,9b-tetrahydro-2-p-(methoxyphenacyl-)5-methyl-2H-indeno(1,2-c)pyridine.22. The compound of claim 1, which is2-(3-p-chlorophenyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 23. The compound of claim 1, which is2-(3-p-bromophenyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 24. The compound of claim 1, which is1,3,4,9b-tetrahydro-2-(3-p-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indeno(1,2-c)pyridine.25. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(3-oxo-3-phenylpropyl)-2H-indeno(1,2-c)pyridine.
 26. The compound of claim 1, which is2-(3-p-fluorophenyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 27. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-2-(3-oxo-3-m-tolylpropyl)-2H-indeno(1,2-c)pyridine.
 28. The compound of claim 1, which is1,3,4,9b-tetrahydro-5-methyl-(3-oxo-3-o-tolylpropyl)-2H-indeno(1,2-c)pyridine.
 29. The compound of claim 1, which is1,3,4,9b-tetrahydro-2-(3-m-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indeno(1,2-c)pyridine.30. A free base of the formula:
 31. The compound of claim 30, which is2-(3-p-chlorophenyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)-pyridine.
 32. The compound of claim 30, which is2-(3-p-bromophenyl-3-oxopropyl)-1,3,4,9b-tetrahydro-5-methyl-2H-indeno(1,2-c)pyridine.
 33. The compound of claim 30, which is1,3,4,9b-tetrahydro-2-(3-p-methoxyphenyl-3-oxopropyl)-5-methyl-2H-indeno(1,2-c)pyridine.